The vascular system contains vessels that are morphologically and functionally distinct. For example, arteries carry oxygenated blood at high pressure from the heart, while veins serve as capacitance vessels for blood return. While some of the differences within the vascular system occur after the onset of function, a complete vascular loop, formed by the trunk artery and vein, is required to accommodate the output of the first heart beat. The major trunk vessels, the aorta and the axial vein, of vertebrate embryos are formed by the coalescence of scattered mesodermal angioblasts into simple endothelial tubes by a process termed “vasculogenesis,” which is distinguished from “angiogenesis,” the formation of vessels by sprouting and remodeling (Fishman, “Assembly of blood vessels in the embryos,” Lippincott-Raven Publishers, Philadelphia, 1996; Folkman et al., Cell 87:1153-1155, 1996; Risau, Nature 386:671-674, 1997; Yancopolos et al., Cell 93:661-664, 1998).
The aorta, the main trunk of the systemic arterial network, is subject to several congenital and acquired disorders, that may lead to severe complications in infancy and adulthood. Coarctation of the aorta is one of the most common human congenital cardiovascular diseases. In coarctation, a discrete, localized vascular malformation partially obstructs the descending aorta, the major artery to the body, and most frequently occurs distal to the origins of vessels supplying the head and arms. Its effects often become more physiologically severe at birth, when closure of the ductus can exacerbate the restriction to aortic blood flow. As a consequence of coarctation, affected individuals suffer from high blood pressure in the upper extremities and head, and from low pressure in the trunk and legs. Survival often depends on the development of collateral blood vessels, which facilitate blood circulation in a manner so as to bypass the lesion.
Another serious cardiovascular disease that affects large numbers of individuals is atherosclerosis. This condition is characterized by the deposition of lipids in the intima of large and medium-sized arteries. Such deposits are associated with fibrosis and calcification.
The gridlock mutation (grlm145) is a recessive mutation that was identified in the zebrafish system and that causes a focal vascular malformation resembling coarctation of the aorta in humans. In grlm145 mutant embryos, fluorescent dextran injected into the heart, to outline patent vessels, is blocked at the origin of the dorsal aorta at the region where the two anterior dorsal aortae merge to form the single aorta of the trunk. The fluorescent beads circulated normally in the head (Weinstein et al., Nature Medicine 1:1143-1147, 1995). Thus, the grl mutant embryos lack circulation to the trunk.